Abstract Traumatic brain injury (TBI) is a leading cause of death and long-term disability in the developed world. By far the majority of TBIs are mild to moderate in nature and account for 80?95 % of cases, with severe TBI comprising the remainder. With increases in survival following initial injury, TBI can result in substantial and lifelong cognitive, physical, and behavioral impairments that require long-term access to health care and disability services. Particularly vulnerable are the elderly, in which the same insult results in greater disability and can result in a dramatic increase in the risk of neurodegenerative and neuropsychiatric disorders. TBI can occasionally resolve within the first year after injury, but 70-90% of patients continue to manifest prolonged and often permanent neurocognitive dysfunctions that can substantially impact their performance and/or quality of life. Emerging evidence indicates that this process can lead to early dementia onset. Clinically, TBI is one of the most powerful environmental risk factors for development of Alzheimer's disease (AD). We propose to study the role of apoptosis in brain injury involving downstream effects of p53 activation using PFT compounds. Our studies will involve behavioral, cellular and molecular indices of injury and if p53 inhibitors will provide neuroprotection. Since there is increasing epidemiological and experimental evidence that TBI may lead to subsequent dementia and Alzheimer's disease-like neuropathological changes in man, we will study long-term effects of moderate TBI in wild type and AD (APP/PSI) mice using the parameters described in Aim/Expt 1. In addition to the behavioral and cellular studies in Aims 1 & 2, we will measure ?AD indices? such as APP, A?, and Tau (both total and Cis phospho Tau), both biochemically and histochemically. Together, the combined pharmacological and genetic approach in this proposal will generate data that will provide insights on the precise role of p53 transcriptional or mitochondrial pathways in the process of TBI-induced cell death. The data gained will be directly applicable to developing novel therapeutic interventions in treating TBI through the modulation of acute or long-term cell death in the CNS.